Over-expression of Human Epidermal Growth Factor Receptor 2 (HER2)—also known as NEU, ERBB-2, CD340, or p185—is associated with a variety of cancers including, e.g., breast cancer, ovarian cancer, stomach cancer, uterine cancer, melanoma, and cholangiocarcinoma. For example, HER2 over-expression is typically associated with aggressive, metastatic forms of breast cancer that have high rates of recurrence and/or are associated with poor patient prognosis.
Anthracyclines have been used as effective cancer therapies for decades, and anthracycline-based regimens have demonstrated clinical benefit for treating breast cancer. Unfortunately, such anthracycline-based regimens are associated with significant toxicities such as, for example, acute and/or chronic cardiac dysfunction, which have limited their therapeutic use. In an effort to improve the safety and efficacy of currently available anthracyclines, immunoliposomal formulations have been prepared that contain the anthracycline doxorubicin in liposomes having antibodies in their exterior surfaces that target HER2 overexpressing cancer cells and do not block (e.g., the antibodies do not block) HER2-mediated signaling.
Another approach to treating HER2 overexpressing cancers has focused on the use of anti-HER2 antibodies that inhibit HER2 signaling. For example, trastuzumab (HERCEPTIN®) is a therapeutic anti-HER2 antibody that blocks intracellular signaling mediated by HER2 and is widely used to treat HER2 overexpressing tumors. Unfortunately, a key dosage-limiting effect of trastuzumab is cardiotoxicity. Cardiomyocytes are known to express HER2, and trastuzumab-mediated cardiotoxicity is generally believed to result from damage to HER2-expressing cardiomyocytes that results from trastuzumab binding to the cardiomyocyte-expressed HER2. As both anthracycline drugs and anti-HER2 antibodies are associated with related serious side effects (i.e., cardiotoxicity), there remains a critical need to optimize established therapies and develop new, therapies that will provide better anti-cancer effects with fewer adverse effects on the heart and thereby prolong patients' lives with reduced negative impacts on quality of life.